FDA Panel Nixes Hemispherx CFS Drug

SILVER SPRING, Md. -- An FDA advisory panel voted 8-5 against recommending approval for the drug rintatolimod (Ampligen) for use in chronic fatigue syndrome (CFS), citing questionable clinical trial results that were based on a small number of patients.

Rintatolimod only met its primary endpoint in a confirmatory study after a post-hoc analysis of patients who had CFS for less than 10 years. Excluding 37 patients from the 234-patient trial significantly improved patient outcomes in exercise tolerance testing but also caused the P-value to slip outside the range showing clinical significance.

Members of the agency's Arthritis Advisory Committee voiced confidence that rintatolimod may work in a small group of CFS patients, but that wasn't shown clearly by its manufacturer, Philadelphia-based Hemispherx.

"There's probably a subgroup where this works," Gailen Marshall, MD, PhD, medical professor at the University of Mississippi Medical Center, said. "It's just not for everyone."

Some panelists questioned -- as the FDA did in briefing documents released before the meeting -- differing results from two phase III trials. In one, a double-blinded, placebo controlled, randomized trial of 92 patients demonstrated a slight benefit, but that benefit was only shown after data was transformed by a logarithmic scale.

Patients in that trial receiving rintatolimod over placebo showed an average 10-point change in the Karnofsky Performance Scale (KPS), a scale of 0 to 100 that assesses functional impairment (P=0.02).

"What we need is two studies that have adequate sample size and the same endpoint," said Irwin Russell, MD, PhD, director of fibromyalgia research at the Arthritis & Osteoporosis Center of South Texas in San Antonio.

CFS is defined as 6 or more consecutive months of profound fatigue that is not improved by bed rest and is worsened by mental or physical activity. Treatment options are limited and there are no approved therapies, the FDA said. It afflicts one in 4 million people, according to the CDC.

Many panelists including chairperson Lenore Buckley, MD, professor of internal medicine at the Yale School of Medicine, questioned the lack of long-term studies for a drug that could be given to patients for the rest of their life.

The FDA also said a few patients account for all the treatment difference.

The FDA also questioned the single dose -- 400 mg -- studied in the drug. "It does limit our ability to interpret much of the data that you see," Theresa Michele, MD, clinical team leader of the FDA's pulmonology products division, said.

Rintatolimod is a twice-weekly intravenous infusion.

Panel members were heavily swayed by nearly 2 hours of compelling patient testimony from patients during the meeting's public hearing portion. Even panelists who voted no said they didn't want to keep the drug from patients who might be helped, although it might be just a small group.

The FDA's analysis also found discrepancies in the drug's safety data -- so much so that FDA officials called what Hemispherx submitted unreliable.

"As we reviewed the sponsor's data, we found multiple areas of discrepancies," Michele said. "Every time, we see that it raises our eyebrows a little bit and makes us question whatever else is in the packet."

The agency noted that patients taking the drug may be at increased risk for thrombosis, major cardiac events, malignancy, liver function, and abdominal pain.

Hemispherx officials said they believe the safety issues the FDA raised -- for the first time in nearly 20 years of development -- are unfounded and could be resolved by a more thorough review of its data.

"We would be pleased to sit down with the FDA reviewers to discuss these issues," Hemispherx Chief Executive William Carter said Thursday.

For example, Hemispherx said the FDA counted single adverse events as multiple ones, and also counted benign tumors and malignancies. The drugmaker also said there was no increased risk of death or suicide from the drug. The FDA noted three deaths, two of them suicides.

One patient had a lupus flare, which the FDA counted as an adverse event. The drugmaker said the patient had lupus before the trial started, but having that condition should have disqualified the patient from participating.

The FDA is expected to render its decision on the drug by Feb. 3. The agency isn't required to follow the advice of its advisory committees, but usually does.

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